Prodrugs of fumarates and their use in treating various diseases

ABSTRACT

The invention also provides pharmaceutical compositions and methods for treating neurological diseases, such as multiple sclerosis.

RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.14/744,325, filed Jun. 19, 2015, which is a continuation of U.S.application Ser. No. 14/180,687, filed Feb. 14, 2014, now U.S. Pat. No.9,090,558, issued Jul. 28, 2015, which claims the benefit of U.S.Provisional Application No. 61/782,445, filed on Mar. 14, 2013. Theentire teachings of the above applications are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to various prodrugs of monomethylfumarate. In particular, the present invention relates to derivatives ofmonomethyl fumarate which offer improved properties relative to dimethylfumarate. The invention also relates to methods of treating variousdiseases.

BACKGROUND OF THE INVENTION

Fumaric acid esters (FAEs) are approved in Germany for the treatment ofpsoriasis, are being evaluated in the United States for the treatment ofpsoriasis and multiple sclerosis, and have been proposed for use intreating a wide range of immunological, autoimmune, and inflammatorydiseases and conditions.

FAEs and other fumaric acid derivatives have been proposed for use intreating a wide-variety of diseases and conditions involvingimmunological, autoimmune, and/or inflammatory processes includingpsoriasis (Joshi and Strebel, WO 1999/49858; U.S. Pat. No. 6,277,882;Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdiand Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronicobstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US2007/0027076); cardiac insufficiency including left ventricularinsufficiency, myocardial infarction and angina pectoris (Joshi et al.,WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial andneurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, Huntington's disease, retinopathia pigmentosa and mitochondrialencephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659,U.S. Pat. Nos. 6,509,376, 6,858,750, and 7,157,423); transplantation(Joshi and Strebel, WO 2002/055063, US 2006/0205659, U.S. Pat. Nos.6,359,003, 6,509,376, and 7,157,423; and Lehmann et al., Arch DermatolRes 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO2002/055063, U.S. Pat. Nos. 6,509,376, 7,157,423, and US 2006/0205659)including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 andU.S. Pat. No. 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigket al., Eur J Neurology 2006, 13, 604-610; and Schilling et al., ClinExperimental Immunology 2006, 145, 101-107); ischemia and reperfusioninjury (Joshi et al., US 2007/0027076); AGE-induced genome damage(Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn'sdisease and ulcerative colitis; arthritis; and others (Nilsson et al.,WO 2006/037342 and Nilsson and Muller, WO 2007/042034).

FUMADERM®, an enteric coated tablet containing a salt mixture ofmonoethyl fumarate and dimethyl fumarate (DMF) which is rapidlyhydrolyzed to monomethyl fumarate, regarded as the main bioactivemetabolite, was approved in Germany in 1994 for the treatment ofpsoriasis. FUMADERM® is dosed TID with 1-2 grams/day administered forthe treatment of psoriasis. FUMADERM® exhibits a high degree ofinterpatient variability with respect to drug absorption and foodstrongly reduces bioavailability. Absorption is thought to occur in thesmall intestine with peak levels achieved 5-6 hours after oraladministration. Significant side effects occur in 70-90% of patients(Brewer and Rogers, Clin Expt'l Dermatology 2007, 32, 246-49; andHoefnagel et al., Br J Dermatology 2003, 149, 363-369). Side effects ofcurrent FAE therapy include gastrointestinal upset including nausea,vomiting, diarrhea and/or transient flushing of the skin.

Multiple sclerosis (MS) is an autoimmune disease with the autoimmuneactivity directed against central nervous system (CNS) antigens. Thedisease is characterized by inflammation in parts of the CNS, leading tothe loss of the myelin sheathing around neuronal axons (gradualdemyelination), axonal loss, and the eventual death of neurons,oligodendrocytes and glial cells.

Dimethyl fumarate (DMF) is the active component of the experimentaltherapeutic, BG-12, studied for the treatment of relapsing-remitting MS(RRMS). In a Phase IIb RRMS study, BG-12 significantly reducedgadolinium-enhancing brain lesions. In preclinical studies, DMFadministration has been shown to inhibit CNS inflammation in murine andrat EAE. It has also been found that DMF can inhibit astrogliosis andmicroglial activations associated with EAE. See, e.g., US PublishedApplication No. 2012/0165404.

There are four major clinical types of MS: 1) relapsing-remitting MS(RRMS), characterized by clearly defined relapses with full recovery orwith sequelae and residual deficit upon recovery; periods betweendisease relapses characterized by a lack of disease progression; 2)secondary progressive MS (SPMS), characterized by initial relapsingremitting course followed by progression with or without occasionalrelapses, minor remissions, and plateaus; 3) primary progressive MS(PPMS), characterized by disease progression from onset with occasionalplateaus and temporary minor improvements allowed; and 4) progressiverelapsing MS (PRMS), characterized by progressive disease onset, withclear acute relapses, with or without full recovery; periods betweenrelapses characterized by continuing progression.

Clinically, the illness most often presents as a relapsing-remittingdisease and, to a lesser extent, as steady progression of neurologicaldisability. Relapsing-remitting MS (RRMS) presents in the form ofrecurrent attacks of focal or multifocal neurologic dysfunction. Attacksmay occur, remit, and recur, seemingly randomly over many years.Remission is often incomplete and as one attack follows another, astepwise downward progression ensues with increasing permanentneurological deficit. The usual course of RRMS is characterized byrepeated relapses associated, for the majority of patients, with theeventual onset of disease progression. The subsequent course of thedisease is unpredictable, although most patients with arelapsing-remitting disease will eventually develop secondaryprogressive disease. In the relapsing-remitting phase, relapsesalternate with periods of clinical inactivity and may or may not bemarked by sequelae depending on the presence of neurological deficitsbetween episodes. Periods between relapses during therelapsing-remitting phase are clinically stable. On the other hand,patients with progressive MS exhibit a steady increase in deficits, asdefined above and either from onset or after a period of episodes, butthis designation does not preclude the further occurrence of newrelapses.

Notwithstanding the above, dimethyl fumarate is also associated withsignificant drawbacks.

For example, dimethyl fumarate is known to cause side effects upon oraladministration, such as flushing and gastrointestinal events including,nausea, diarrhea, and/or upper abdominal pain in subjects. See, e.g.,Gold et al., N. Eng. J. Med., 2012, 367(12), 1098-1107. Dimethylfumarate is dosed BID or TID with a total daily dose of about 480 mg toabout 1 gram or more.

Further, in the use of a drug for long-term therapy it is desirable thatthe drug be formulated so that it is suitable for once- or twice-dailyadministration to aid patient compliance. A dosing frequency ofonce-daily or less is even more desirable.

Another problem with long-term therapy is the requirement of determiningan optimum dose which can be tolerated by the patient. If such a dose isnot determined this can lead to a diminution in the effectiveness of thedrug being administered.

Accordingly, it is an object of the present invention to providecompounds and/or compositions which are suitable for long-termadministration.

It is a further object of the present invention to provide the use of apharmaceutical active agent in a manner which enables one to achieve atolerable steady state level for the drug in a subject being treatedtherewith.

Because of the disadvantages of dimethyl fumarate described above, therecontinues to be a need to decrease the dosing frequency, reduceside-effects and/or improve the physicochemical properties associatedwith DMF. There remains, therefore, a real need in the treatment ofneurological diseases, such as MS, for a product which retains thepharmacological advantages of DMF but overcomes its flaws in formulationand/or adverse effects upon administration. The present inventionaddresses these needs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showingvinylic region, as observed by NMR over 90 minutes.

FIG. 2 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showingvinylic region, as observed by NMR over 19 hours.

FIG. 3 depicts the hydrolysis of Compound 16 at pH 7.9, 25° C., showingaliphatic region, as observed by NMR over 19 hours.

FIG. 4 depicts the hydrolysis of Reference Compound A at pH 7.9, 37° C.,showing vinylic region, as observed by NMR over 15 hours.

FIG. 5 depicts the hydrolysis of Reference Compound A at pH 7.9, 37° C.,showing aliphatic region, as observed by NMR over 15 hours.

SUMMARY OF THE INVENTION

This invention is directed to the surprising and unexpected discovery ofnovel prodrugs and related methods useful in the treatment ofneurological diseases. The methods and compositions described hereincomprise one or more prodrugs (e.g., aminoalkyl prodrugs) of monomethylfumarate (MMF). The methods and compositions provide for atherapeutically effective amount of an active moiety in a subject for atime period of at least about 8 hours to at least about 24 hours.

More specifically, the compounds of the invention can be converted invivo, upon oral administration, to monomethyl fumarate. Upon conversion,the active moiety (i.e., monomethyl fumarate) is effective in treatingsubjects suffering from a neurological disease.

The present invention provides, in part, a compound of Formula (I), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

wherein:

-   -   R₁ is unsubstituted C₁-C₆ alkyl;    -   L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker,        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S; and    -   R₂ and R₃ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        C₃-C₁₀ carbocycle, substituted or unsubstituted heterocycle        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O and S, or substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S;    -   or alternatively, R₂ and R₃, together with the nitrogen atom to        which they are attached, form a substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S or a substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of any of the formulae described hereinand one or more pharmaceutically acceptable carriers.

The present invention also provides methods of treating a neurologicaldisease by administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of any of the formulae described herein,or a pharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof, such that the disease is treated.

The present invention also provides methods of treating multiplesclerosis by administering to a subject in need thereof, atherapeutically effective amount of a compound of any of the formulaedescribed herein, or a pharmaceutically acceptable salt, polymorph,hydrate, solvate or co-crystal thereof, such that the multiple sclerosisis treated.

The present invention also provides methods of treatingrelapsing-remitting multiple sclerosis (RRMS) by administering to asubject in need thereof, a therapeutically effective amount of acompound of any of the formulae described herein, or a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate or co-crystal thereof, suchthat the multiple sclerosis is treated.

The present invention also provides methods of treating secondaryprogressive multiple sclerosis (SPMS) by administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe formulae described herein, or a pharmaceutically acceptable salt,polymorph, hydrate, solvate or co-crystal thereof, such that themultiple sclerosis is treated.

The present invention also provides methods of treating primaryprogressive multiple sclerosis (PPMS) by administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe formulae described herein, or a pharmaceutically acceptable salt,polymorph, hydrate, solvate or co-crystal thereof, such that themultiple sclerosis is treated.

The present invention also provides methods of treating progressiverelapsing multiple sclerosis (PRMS) by administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe formulae described herein, or a pharmaceutically acceptable salt,polymorph, hydrate, solvate or co-crystal thereof, such that themultiple sclerosis is treated.

The present invention also provides methods of treating Alzheimer'sdisease by administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of any of the formulae described herein,or a pharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof, such that the Alzheimer's disease is treated.

The present invention also provides methods of treating cerebral palsyby administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of any of the formulae described herein,or a pharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof, such that the cerebral palsy is treated.

The present invention also provides compounds and compositions thatenable improved oral, controlled- or sustained-release formulations.Specifically, dimethyl fumarate is administered twice or three timesdaily for the treatment of relapsing-remitting multiple sclerosis. Incontrast, the compounds and compositions of the present invention mayenable formulations with a modified duration of therapeutic efficacy forreducing relapse rates in subjects with multiple sclerosis. For example,the present compounds and compositions provide therapeutically effectiveamounts of monomethyl fumarate in subjects for at least about 8 hours,at least about 12 hours, at least about 16 hours, at least about 20hours or at least about 24 hours.

The present invention also provides compounds, compositions and methodswhich may result in decreased side effects upon administration to asubject relative to dimethyl fumarate. For example, gastric irritationand flushing are known side effects of oral administration of dimethylfumarate in some subjects. The compounds, compositions and methods ofthe present invention can be utilized in subjects that have experiencedor are at risk of developing such side effects.

The present invention also provides for compounds and compositions whichexhibit improved physical stability relative to dimethyl fumarate.Specifically, dimethyl fumarate is known in the art to undergosublimation at ambient and elevated temperature conditions. Thecompounds of the invention possess greater physical stability thandimethyl fumarate under controlled conditions of temperature andrelative humidity. Specifically, in one embodiment, the compounds of theformulae described herein exhibit decreased sublimation relative todimethyl fumarate.

Further, dimethyl fumarate is also known to be a contact irritant. Seee.g., Material Safety Data Sheet for DMF. In one embodiment, thecompounds of the present invention exhibit reduced contact irritationrelative to dimethyl fumarate. For example, the compounds of theformulae described herein exhibit reduced contact irritation relative todimethyl fumarate.

The present invention also provides for compounds and compositions whichexhibit decreased food effect relative to dimethyl fumarate. Thebioavailability of dimethyl fumarate is known in the art to be reducedwhen administered with food. Specifically, in one embodiment, thecompounds of the formulae described herein exhibit decreased food effectrelative to dimethyl fumarate.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds and methods of treating aneurological disease by administering a compound of Formula (I), (Ia),(Ib), (II) or (III), synthetic methods for making a compound of Formula(I), (Ia), (Ib), (II) or (III), and pharmaceutical compositionscontaining a compound of Formula (I), (Ia), (Ib), (II) or (III).

The present invention also provides compounds and methods for thetreatment of psoriasis by administering to a subject in need thereof, atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II) or (III), or a pharmaceutically acceptable salt, polymorph,hydrate, solvate or co-crystal thereof.

The present invention provides, in part, methods for the treatment of aneurological disease by administering to a subject in need thereof, atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II) or (III), or a pharmaceutically acceptable salt, polymorph,hydrate, solvate or co-crystal thereof. The neurological disease can bemultiple sclerosis. The present invention further provides the use of acompound of Formula (I), (Ia), (Ib), (II) or (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof, for the preparation of a medicament useful for thetreatment of a neurological disease.

According to the present invention, a neurological disease is a disorderof the brain, spinal cord or nerves in a subject. In one embodiment, theneurological disease is characterized by demyelination, or degenerationof the myelin sheath, of the central nervous system. The myelin sheathfacilitates the transmission of nerve impulses through a nerve fiber oraxon. In another embodiment, the neurological disease is selected fromthe group consisting of multiple sclerosis, Alzheimer's disease,cerebral palsy, spinal cord injury, Amyotrophic lateral sclerosis (ALS),stroke, and Huntington's disease, Parkinson's disease, optic neuritis,Devic disease, transverse myelitis, acute disseminatedencephalomyelitis, adrenoleukodystrophy and adrenomyeloneuropathy, acuteinflammatory demyelinating polyneuropathy (AIDP), chronic inflammatorydemyelinating polyneuropathy (CIDP), acute transverse myelitis,progressive multifocal leucoencephalopathy (PML), acute disseminatedencephalomyelitis (ADEM) and other hereditary disorders, such asleukodystrophies, Leber's optic atrophy, and Charcot-Marie-Toothdisease. In some embodiments, the neurological disorder is anauto-immune disease. In one embodiment, the neurological disease ismultiple sclerosis. In another embodiment, the neurological disease isstroke. In another embodiment, the neurological disease is Alzheimer'sdisease. In another embodiment, the neurological disease is cerebralpalsy. In another embodiment, the neurological disease is spinal cordinjury. In another embodiment, the neurological disease is ALS. Inanother embodiment, the neurological disease is Huntington's disease.See, e.g., U.S. Pat. No. 8,007,826, WO2005/099701 and WO2004/082684,which are incorporated by reference in their entireties.

In a further embodiment, the present invention provides methods for thetreatment of a disease or a symptom of a disease described herein byadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (II) or (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof. The present invention further provides the use of acompound of Formula (I), (Ia), (Ib), (II) or (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof, for the preparation of a medicament useful for thetreatment of a disease or a symptom of a disease described herein.

In another embodiment, the present invention provides a compound ofFormula (I), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate or co-crystal thereof, or a method for the treatment of aneurological disease by administering to a subject in need thereof, atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

wherein:

-   -   R₁ is unsubstituted C₁-C₆ alkyl;    -   L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker,        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S; and    -   R₂ and R₃ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        C₃-C₁₀ carbocycle, substituted or unsubstituted heterocycle        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O and S, or substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S;    -   or alternatively, R₂ and R₃, together with the nitrogen atom to        which they are attached, form a substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S or a substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiplesclerosis (RRMS).

For example, the compound of Formula (I) is a compound listed in Table 1herein.

For example, in the compound of Formula (I), R₁ is methyl.

For example, in the compound of Formula (I), R₁ is ethyl.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (I), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is methyl substitutedor unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (I), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (I), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (I), R₂ isC(O)OR_(a)-substitutedC₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (I), R₂ isS(O)(O)R_(b)-substitutedC₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (I), R₃ is H.

For example, in the compound of Formula (I), R₃ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (I), R₃ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, or a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpiperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a halogen substitutedpiperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a 4-halogensubstituted piperidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedmorpholinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpyrrolidinyl ring.

For example, in the compound of Formula (I), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5 or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (I), R₂ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (I), R₂ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (I), R₂ is unsubstituted phenyl.

For example, in the compound of Formula (I), R₂ is unsubstituted benzyl.

In another embodiment, the present invention provides a compound ofFormula (Ia), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate or co-crystal thereof, or a method for the treatment of aneurological disease by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (Ia), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

wherein:

-   -   R₁ is unsubstituted C₁-C₆ alkyl;    -   L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker,        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S; and    -   R₂ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted        or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted        C₂-C₆ alkynyl, substituted or unsubstituted C₆-C₁₀ aryl,        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S, or        substituted or unsubstituted heteroaryl comprising one or two 5-        or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiplesclerosis (RRMS).

For example, in the compound of Formula (Ia), R₁ is methyl.

For example, in the compound of Formula (Ia), R₁ is ethyl.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (Ia), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (Ia), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ia), R₂ is methyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ia), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (Ia), R₂ isC(O)OR_(a)-substitutedC₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ia), R₂ isS(O)(O)R_(b)-substitutedC₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

In another embodiment, the present invention provides a compound ofFormula (Ib), or a pharmaceutically acceptable polymorph, hydrate,solvate or co-crystal thereof, or a method for the treatment of aneurological disease by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (Ib), or apharmaceutically acceptable polymorph, hydrate, solvate or co-crystalthereof:

-   -   A⁻ is a pharmaceutically acceptable anion;    -   R₁ is unsubstituted C₁-C₆ alkyl;    -   L_(a) is substituted or unsubstituted C₁-C₆ alkyl linker,        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S;    -   R₃′ is substituted or unsubstituted C₁-C₆ alkyl; and    -   R₂ and R₃ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        C₃-C₁₀ carbocycle, substituted or unsubstituted heterocycle        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O and S, or substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S;    -   or alternatively, R₂ and R₃, together with the nitrogen atom to        which they are attached, form a substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or a substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiplesclerosis (RRMS).

For example, in the compound of Formula (Ib), R₁ is methyl.

For example, in the compound of Formula (Ib), R₁ is ethyl.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₁-C₆ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₁-C₃ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is substituted orunsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is di-methylsubstituted or unsubstituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is methyl ordi-methyl substituted C₂ alkyl linker.

For example, in the compound of Formula (Ib), L_(a) is unsubstituted C₂alkyl linker.

For example, in the compound of Formula (Ib), R₂ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (Ib), R₂ isC(O)OR_(a)-substitutedC₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₂ isS(O)(O)R_(b)-substitutedC₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₃ is H.

For example, in the compound of Formula (Ib), R₃ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (Ib), R₃ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S, or a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl,piperazinyl, or morpholinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted piperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpiperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a halogen substitutedpiperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a 4-halogensubstituted piperidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedmorpholinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form an unsubstitutedpyrrolidinyl ring.

For example, in the compound of Formula (Ib), R₂ and R₃, together withthe nitrogen atom to which they are attached, form a substituted orunsubstituted heteroaryl comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S.

For example, in the compound of Formula (Ib), R₂ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (Ib), R₂ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (Ib), R₂ is unsubstitutedphenyl.

For example, in the compound of Formula (Ib), R₂ is unsubstitutedbenzyl.

For example, in the compound of Formula (Ib), R₃′ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (Ib), R₃′ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (Ib), R₃′ is methyl.

In one embodiment, the present invention provides a compound of Formula(II), or a pharmaceutically acceptable salt, polymorph, hydrate, solvateor co-crystal thereof, or a method for the treatment of a neurologicaldisease by administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (II), or a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate or co-crystal thereof:

wherein:

-   -   R₁ is unsubstituted C₁-C₆ alkyl;    -   R₄ and R₅ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₆-C₁₀ aryl, substituted or unsubstituted        C₃-C₁₀ carbocycle, substituted or unsubstituted heterocycle        comprising one or two 5- or 6-member rings and 1-4 heteroatoms        selected from N, O and S, or substituted or unsubstituted        heteroaryl comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S;    -   R₆, R₇, R₈ and R₉ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl or        C(O)OR_(a); and    -   R_(a) is H or substituted or unsubstituted C₁-C₆ alkyl.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiplesclerosis (RRMS).

For example, in the compound of Formula (II), R₁ is methyl.

For example, in the compound of Formula (II), R₁ is ethyl.

For example, in the compound of Formula (II), R₄ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₃alkyl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₁-C₂alkyl.

For example, in the compound of Formula (II), R₄ isC(O)OR_(a)-substitutedC₁-C₆ alkyl, wherein R_(a) is H or unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (II), R₄ isS(O)(O)R_(b)-substitutedC₁-C₆ alkyl, wherein R_(b) is unsubstitutedC₁-C₆ alkyl.

For example, in the compound of Formula (II), R₅ is H.

For example, in the compound of Formula (II), R₅ is substituted orunsubstituted C₁-C₆ alkyl.

For example, in the compound of Formula (II), R₅ is unsubstituted C₁-C₆alkyl.

For example, in the compound of Formula (II), R₄ is substituted orunsubstituted C₆-C₁₀ aryl.

For example, in the compound of Formula (II), R₄ is unsubstituted C₆-C₁₀aryl.

For example, in the compound of Formula (II), R₄ is unsubstitutedphenyl.

For example, in the compound of Formula (II), R₄ is unsubstitutedbenzyl.

For example, in the compound of Formula (II), R₆, R₇, R₈ and R₉ are eachH.

For example, in the compound of Formula (II), R₆ is substituted orunsubstituted C₁-C₆ alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₆ is unsubstituted C₁-C₆alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₈ is substituted orunsubstituted C₁-C₆ alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₈ is unsubstituted C₁-C₆alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₆ and R₈ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₇ and R₉are each H.

For example, in the compound of Formula (II), R₆ and R₈ are each,independently, unsubstituted C₁-C₆ alkyl and R₇ and R₉ are each H.

For example, in the compound of Formula (II), R₆ and R₇ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₈ and R₉are each H.

For example, in the compound of Formula (II), R₆ and R₇ are each,independently, unsubstituted C₁-C₆ alkyl and R₈ and R₉ are each H.

For example, in the compound of Formula (II), R₈ and R₉ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₆ and R₇are each H.

For example, in the compound of Formula (II), R₈ and R₉ are each,independently, unsubstituted C₁-C₆ alkyl and R₆ and R₇ are each H.

In one embodiment, the present invention provides a compound of Formula(III), or a pharmaceutically acceptable salt, polymorph, hydrate,solvate or co-crystal thereof, or a method for the treatment of aneurological disease by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (III), or apharmaceutically acceptable salt, polymorph, hydrate, solvate orco-crystal thereof:

wherein:

-   -   R₁ is unsubstituted C₁-C₆ alkyl;

-   -    is selected from the group consisting of:

-   -   X is N, O, S or SO₂;    -   Z is C or N;    -   m is 0, 1, 2, or 3;    -   n is 1 or 2;    -   w is 0, 1, 2 or 3;    -   t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;    -   R₆, R₇, R₈ and R₉ are each, independently, H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl or        C(O)OR_(a); and    -   R_(a) is H or substituted or unsubstituted C₁-C₆ alkyl; and    -   each R₁₀ is, independently, H, halogen, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₂-C₆        alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, substituted        or unsubstituted C₃-C₁₀ carbocycle, substituted or unsubstituted        heterocycle comprising one or two 5- or 6-member rings and 1-4        heteroatoms selected from N, O and S, or substituted or        unsubstituted heteroaryl comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S;    -   or, alternatively, two R₁₀'s attached to the same carbon atom,        together with the carbon atom to which they are attached, form a        carbonyl, substituted or unsubstituted C₃-C₁₀ carbocycle,        substituted or unsubstituted heterocycle comprising one or two        5- or 6-member rings and 1-4 heteroatoms selected from N, O and        S, or substituted or unsubstituted heteroaryl comprising one or        two 5- or 6-member rings and 1-4 heteroatoms selected from N, O        and S;    -   or, alternatively, two R₁₀'s attached to different atoms,        together with the atoms to which they are attached, form a        substituted or unsubstituted C₃-C₁₀ carbocycle, substituted or        unsubstituted heterocycle comprising one or two 5- or 6-member        rings and 1-4 heteroatoms selected from N, O and S, or        substituted or unsubstituted heteroaryl comprising one or two 5-        or 6-member rings and 1-4 heteroatoms selected from N, O and S.

For example, the neurological disease is multiple sclerosis.

For example, the neurological disease is relapsing-remitting multiplesclerosis (RRMS).

For example, in the compound of Formula (III), R₁ is methyl.

For example, in the compound of Formula (III), R₁ is ethyl.

For example, in the compound of Formula (III),

For example, in the compound of Formula (III),

For example, in the compound of Formula (III),

For example, in the compound of Formula (III),

For example, in the compound of Formula (III), R₆ is substituted orunsubstituted C₁-C₆ alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₆ is unsubstituted C₁-C₆alkyl and R₇, R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₈ is substituted orunsubstituted C₁-C₆ alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₈ is unsubstituted C₁-C₆alkyl and R₆, R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₆ and R₈ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₇ and R₉are each H.

For example, in the compound of Formula (III), R₆ and R₈ are each,independently, unsubstituted C₁-C₆ alkyl and R₇ and R₉ are each H.

For example, in the compound of Formula (III), R₆ and R₇ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₈ and R₉are each H.

For example, in the compound of Formula (III), R₆ and R₇ are each,independently, unsubstituted C₁-C₆ alkyl and R₈ and R₉ are each H.

For example, in the compound of Formula (III), R₈ and R₉ are each,independently, substituted or unsubstituted C₁-C₆ alkyl and R₆ and R₇are each H.

For example, in the compound of Formula (III), R₈ and R₉ are each,independently, unsubstituted C₁-C₆ alkyl and R₆ and R₇ are each H.

For example, the compound is a compound listed in Table 1 herein.

Representative compounds of the present invention include compoundslisted in Table 1.

TABLE 1 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

A⁻ is a pharmaceutically acceptable anion.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of Formula (I), (Ia), (Ib), (II) or(III) and one or more pharmaceutically acceptable carriers.

In one embodiment, the pharmaceutical composition is a controlledrelease composition comprising a compound of Formula (I), (Ia), (Ib),(II) or (III) and one or more pharmaceutically acceptable carriers,wherein the controlled release composition provides a therapeuticallyeffective amount of monomethyl fumarate to a subject. In anotherembodiment, the pharmaceutical composition is a controlled releasecomposition comprising a compound of Formula (I), (Ia), (Ib), (II) or(III) and one or more pharmaceutically acceptable carriers, wherein thecontrolled release composition provides a therapeutically effectiveamount of monomethyl fumarate to a subject for at least about 8 hours toat least about 24 hours.

In another embodiment, the pharmaceutical composition is a controlledrelease composition comprising a compound of Formula (I), (Ia), (Ib),(II) or (III) and one or more pharmaceutically acceptable carriers,wherein the controlled release composition provides a therapeuticallyeffective amount of monomethyl fumarate to a subject for at least about8 hours, at least about 10 hours, at least about 12 hours, at leastabout 13 hours, at least about 14 hours, at least about 15 hours, atleast about 16 hours, at least about 17 hours, at least about 18 hours,at least about 19 hours, at least about 20 hours, at least about 21hours, at least about 22 hours, at least about 23 hours or at leastabout 24 hours or longer. For example, at least about 18 hours. Forexample, at least about 12 hours. For example, greater than 12 hours.For example, at least about 16 hours. For example, at least about 20hours. For example, at least about 24 hours.

In another embodiment, a compound of Formula (I), (Ia), (Ib), (II) or(III) is efficiently converted to the active species, i.e., monomethylfumarate, upon oral administration. For example, about 50 mole percent,about 55 mole percent, about 60 mole percent, about 65 mole percent,about 70 mole percent, about 75 mole percent, about 80 mole percent,about 85 mole percent, about 90 mole percent, or greater than 90 molepercent of the total dose of a compound of Formula (I), (Ia), (Ib), (II)or (III) administered is converted to monomethyl fumarate upon oraladministration. In another embodiment, a compound of Formula (I), (Ia),(Ib), (II) or (III) is converted to the active species, i.e., monomethylfumarate, upon oral administration more efficiently than dimethylfumarate. In another embodiment, a compound of Formula (I), (Ia), (Ib),(II) or (III) is converted to the active species, i.e., monomethylfumarate, upon oral administration more efficiently than one or more ofthe compounds described in U.S. Pat. No. 8,148,414. For example, acompound of Formula (I), (Ia), (Ib), (II) or (III) is essentiallycompletely converted to the active species, i.e., monomethyl fumarate,upon oral administration. U.S. Pat. No. 8,148,414 is expresslyincorporated by reference herein.

In another embodiment, any one of Compounds 1-20 is efficientlyconverted to the active species, i.e., monomethyl fumarate, upon oraladministration. For example, about 50 percent, about 55 percent, about60 percent, about 65 percent, about 70 percent, about 75 percent, about80 percent, about 85 percent, about 90 percent, or greater than 90percent of the total dose of any one of Compounds 1-20 administered isconverted to monomethyl fumarate upon oral administration. In anotherembodiment, any one of Compounds 1-20 is converted to the activespecies, i.e., monomethyl fumarate, upon oral administration moreefficiently than dimethyl fumarate. In another embodiment, any one ofCompounds 1-20 is converted to the active species, i.e., monomethylfumarate, upon oral administration more efficiently than one or more ofthe compounds described in U.S. Pat. No. 8,148,414. For example, any oneof Compounds 1-20 is completely converted to the active species, i.e.,monomethyl fumarate, upon oral administration.

For a drug to achieve its therapeutic effect, it is necessary tomaintain the required level of blood or plasma concentration. Manydrugs, including dimethyl fumarate, must be administered multiple timesa day to maintain the required concentration. Furthermore, even withmultiple administrations of such a drug per day, the blood or plasmaconcentrations of the active ingredient may still vary with time, i.e.,at certain time points between administrations there are higherconcentrations of the active ingredient than at other times. Thus, atcertain time points of a 24-hour period, a patient may receivetherapeutically effective amounts of the active ingredient, while atother time points the concentration of the active ingredient in theblood may fall below therapeutic levels. Additional problems with suchdrugs include that multiple dosing a day often adversely affects patientcompliance with the treatment. Therefore, it is desirable to have a drugdosage form wherein the active ingredient is delivered in such acontrolled manner that a constant or substantially constant level ofblood or plasma concentration of the active ingredient can be achievedby one or at most two dosing per day. Accordingly, the present inventionprovides controlled-release formulations as described below. In general,such formulations are known to those skilled in the art or are availableusing conventional methods.

As used herein, “controlled-release” means a dosage form in which therelease of the active agent is controlled or modified over a period oftime. Controlled can mean, for example, sustained, delayed orpulsed-release at a particular time. For example, controlled-release canmean that the release of the active ingredient is extended for longerthan it would be in an immediate-release dosage form, i.e., at leastover several hours.

As used herein, “immediate-release” means a dosage form in which greaterthan or equal to about 75% of the active ingredient is released withintwo hours, or, more specifically, within one hour, of administration.Immediate-release or controlled-release may also be characterized bytheir dissolution profiles.

Formulations may also be characterized by their pharmacokineticparameters. As used herein, “pharmacokinetic parameters” describe the invivo characteristics of the active ingredient over time, including forexample plasma concentration of the active ingredient. As used herein,“C_(max)” means the measured concentration of the active ingredient inthe plasma at the point of maximum concentration. “T_(max)” refers tothe time at which the concentration of the active ingredient in theplasma is the highest. “AUC” is the area under the curve of a graph ofthe concentration of the active ingredient (typically plasmaconcentration) vs. time, measured from one time to another.

The controlled-release formulations provided herein provide desirableproperties and advantages. For example, the formulations can beadministered once daily, which is particularly desirable for thesubjects described herein. The formulation can provide many therapeuticbenefits that are not achieved with corresponding shorter acting, orimmediate-release preparations. For example, the formulation canmaintain lower, more steady plasma peak values, for example, C_(max), soas to reduce the incidence and severity of possible side effects.

Sustained-release dosage forms release their active ingredient into thegastro-intestinal tract of a patient over a sustained period of timefollowing administration of the dosage form to the patient. Particulardosage forms include: (a) those in which the active ingredient isembedded in a matrix from which it is released by diffusion or erosion;(b) those in which the active ingredient is present in a core which iscoated with a release rate-controlling membrane; (c) those in which theactive ingredient is present in a core provided with an outer coatingimpermeable to the active ingredient, the outer coating having anaperture (which may be drilled) for release of the active ingredient;(d) those in which the active ingredient is released through asemi-permeable membrane, allowing the drug to diffuse across themembrane or through liquid filled pores within the membrane; and (e)those in which the active ingredient is present as an ion exchangecomplex.

It will be apparent to those skilled in the art that some of the abovemeans of achieving sustained-release may be combined, for example amatrix containing the active compound may be formed into amultiparticulate and/or coated with an impermeable coating provided withan aperture.

Pulsed-release formulations release the active compound after asustained period of time following administration of the dosage form tothe patient. The release may then be in the form of immediate- orsustained-release. This delay may be achieved by releasing the drug atparticular points in the gastro-intestinal tract or by releasing drugafter a pre-determined time. Pulsed-release formulations may be in theform of tablets or multiparticulates or a combination of both.Particular dosage forms include: (a) osmotic potential triggered release(see U.S. Pat. No. 3,952,741); (b) compression coated two layer tablets(see U.S. Pat. No. 5,464,633); (c) capsules containing an erodible plug(see U.S. Pat. No. 5,474,784); 4. sigmoidal releasing pellets (referredto in U.S. Pat. No. 5,112,621); and (d) formulations coated with orcontaining pH-dependent polymers including shellac, phthalatederivatives, polyacrylic acid derivatives and crotonic acid copolymers.

Dual release formulations can combine the active ingredient in immediaterelease form with additional active ingredient in controlled-releaseform. For example, a bilayer tablet can be formed with one layercontaining immediate release active ingredient and the other layercontaining the active ingredient embedded in a matrix from which it isreleased by diffusion or erosion. Alternatively, one or more immediaterelease beads can be combined with one or more beads which are coatedwith a release rate-controlling membrane in a capsule to give a dualrelease formulation. Sustained release formulations in which the activeingredient is present in a core provided with an outer coatingimpermeable to the active ingredient, the outer coating having anaperture (which may be drilled) for release of the active ingredient,can be coated with drug in immediate release form to give a dual releaseformulation. Dual release formulations can also combine drug inimmediate release form with additional drug in pulsed release form. Forexample, a capsule containing an erodible plug could liberate druginitially and, after a predetermined period of time, release additionaldrug in immediate- or sustained-release form.

In some embodiments, the dosage forms to be used can be provided ascontrolled-release with respect to one or more active ingredientstherein using, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, or microspheres or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the pharmaceutical compositions of the invention.Thus, single unit dosage forms suitable for oral administration, such astablets, capsules, gelcaps, and caplets that are adapted forcontrolled-release are encompassed by the present invention.

Most controlled-release formulations are designed to initially releasean amount of drug that promptly produces the desired therapeutic effect,and gradually and continually release of additional amounts of drug tomaintain this level of therapeutic effect over an extended period oftime. In order to maintain this constant level of drug in the body, thedrug must be released from the dosage form at a rate that will replacethe amount of drug being metabolized and excreted from the body.

Controlled-release of an active ingredient can be stimulated by variousinducers, for example pH, temperature, enzymes, concentration, or otherphysiological conditions or compounds.

Powdered and granular formulations of a pharmaceutical preparation ofthe invention may be prepared using known methods. Such formulations maybe administered directly to a subject, used, for example, to formtablets, to fill capsules, or to prepare an aqueous or oily suspensionor solution by addition of an aqueous or oily vehicle thereto. Each ofthese formulations may further comprise one or more of a dispersingagent, wetting agent, suspending agent, and a preservative. Additionalexcipients, such as fillers, sweeteners, flavoring, or coloring agents,may also be included in these formulations.

A formulation of a pharmaceutical composition of the invention suitablefor oral administration may be prepared or packaged in the form of adiscrete solid dose unit including, but not limited to, a tablet, a hardor soft capsule, a cachet, a troche, or a lozenge, each containing apredetermined amount of the active ingredient. In one embodiment, aformulation of a pharmaceutical composition of the invention suitablefor oral administration is coated with an enteric coat.

A tablet comprising the active ingredient may, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets may be prepared bycompressing, in a suitable device, the active ingredient in a freeflowing form such as a powder or granular preparation, optionally mixedwith one or more of a binder, a lubricant, an excipient, asurface-active agent, and a dispersing agent. Molded tablets may be madeby molding, in a suitable device, a mixture of the active ingredient, apharmaceutically acceptable carrier, and at least sufficient liquid tomoisten the mixture. Pharmaceutically acceptable excipients used in themanufacture of tablets include, but are not limited to, inert diluents,granulating and disintegrating agents, binding agents, and lubricatingagents. Known dispersing agents include, but are not limited to, potatostarch and sodium starch glycollate. Known surface-active agentsinclude, but are not limited to, sodium lauryl sulphate and poloxamers.Known diluents include, but are not limited to, calcium carbonate,sodium carbonate, lactose, microcrystalline cellulose, calciumphosphate, calcium hydrogen phosphate, and sodium phosphate. Knowngranulating and disintegrating agents include, but are not limited to,corn starch and alginic acid. Known binding agents include, but are notlimited to, gelatin, acacia, pre-gelatinized maize starch,polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Knownlubricating agents include, but are not limited to, magnesium stearate,stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods toachieve delayed disintegration in the gastrointestinal tract of asubject, thereby providing sustained release and absorption of theactive ingredient. By way of example, a material such as glycerylmonostearate or glyceryl distearate may be used to coat tablets. Furtherby way of example, tablets may be coated using methods described in U.S.Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to formosmotically-controlled release tablets, optionally, with laser drilling.Tablets may further comprise a sweetener, a flavoring agent, a coloringagent, a preservative, or some combination of these in order to providefor pharmaceutically elegant and palatable formulations.

Hard capsules comprising the active ingredient may be made using aphysiologically degradable composition, such as gelatin or HPMC. Suchhard capsules comprise the active ingredient, and may further compriseadditional ingredients including, for example, an inert solid diluentsuch as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made usinga physiologically degradable composition, such as gelatin. Such softcapsules comprise the active ingredient, which may be mixed with wateror an oil medium such as peanut oil, liquid paraffin, or olive oil.

As used herein, “alkyl”, “C₁, C₂, C₃, C₄, C₅ or C₆alkyl” or “C₁-C₆alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain(linear) saturated aliphatic hydrocarbon groups and C₃, C₄, C₅ or C₆branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆alkyl is intended to include C₁, C₂, C₃, C₄, C₅ and C₆ alkyl groups.Examples of alkyl include, moieties having from one to six carbon atoms,such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.

In certain embodiments, a straight chain or branched alkyl has six orfewer carbon atoms (e.g., C₁-C₆ for straight chain, C₃-C₆ for branchedchain), and in another embodiment, a straight chain or branched alkylhas four or fewer carbon atoms.

As used herein, “alkyl linker” is intended to include C₁, C₂, C₃, C₄, C₅or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups andC₃, C₄, C₅ or C₆ branched saturated aliphatic hydrocarbon groups. Forexample, C₁-C₆ alkyl linker is intended to include C₁, C₂, C₃, C₄, C₅and C₆alkyl linker groups. Examples of alkyl linker include, moietieshaving from one to six carbon atoms, such as, but not limited to, methyl(—CH₂—), ethyl (—CH₂CH₂—), n-propyl (—CH₂CH₂CH₂—), i-propyl(—CHCH₃CH₂—), n-butyl (—CH₂CH₂CH₂CH₂—), s-butyl (—CHCH₃CH₂CH₂—), i-butyl(—C(CH₃)₂CH₂—), n-pentyl (—CH₂CH₂CH₂CH₂CH₂—), s-pentyl(—CHCH₃CH₂CH₂CH₂—) or n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₂—). The term“substituted alkyl linker” refers to alkyl linkers having substituentsreplacing one or more hydrogen atoms on one or more carbons of thehydrocarbon backbone. Such substituents do not alter thesp3-hybridization of the carbon atom to which they are attached andinclude those listed below for “substituted alkyl.”

“Heteroalkyl” groups are alkyl groups, as defined above, that have anoxygen, nitrogen, sulfur or phosphorous atom replacing one or morehydrocarbon backbone carbon atoms.

As used herein, the term “cycloalkyl”, “C₃, C₄, C₅, C₆, C₇ or C₈cycloalkyl” or “C₃-C₈ cycloalkyl” is intended to include hydrocarbonrings having from three to eight carbon atoms in their ring structure.In one embodiment, a cycloalkyl group has five or six carbons in thering structure.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing one or more hydrogen atoms on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “aralkyl”moiety is an alkyl substituted with an aryl (e.g.,phenylmethyl(benzyl)).

Unless the number of carbons is otherwise specified, “lower alkyl”includes an alkyl group, as defined above, having from one to six, or inanother embodiment from one to four, carbon atoms in its backbonestructure. “Lower alkenyl” and “lower alkynyl” have chain lengths of,for example, two to six or of two to four carbon atoms.

“Aryl” includes groups with aromaticity, including “conjugated”, ormulticyclic, systems with at least one aromatic ring. Examples includephenyl, benzyl, naphthyl, etc.

“Heteroaryl” groups are aryl groups, as defined above, having from oneto four heteroatoms in the ring structure, and may also be referred toas “aryl heterocycles” or “heteroaromatics”. As used herein, the term“heteroaryl” is intended to include a stable 5-, 6-, or 7-memberedmonocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromaticheterocyclic ring which consists of carbon atoms and one or moreheteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms,independently selected from the group consisting of nitrogen, oxygen andsulfur. The nitrogen atom may be substituted or unsubstituted (i.e., Nor NR wherein R is H or other substituents, as defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), where p=1 or 2). It is to be noted that total number of S andO atoms in the heteroaryl is not more than 1.

Examples of heteroaryl groups include pyrrole, furan, thiophene,thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole,oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and thelike.

Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryland heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, orindolizine.

In the case of multicyclic aromatic rings, only one of the rings needsto be aromatic (e.g., 2,3-dihydroindole), although all of the rings maybe aromatic (e.g., quinoline). The second ring can also be fused orbridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl,naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings arealso included in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. In one embodiment, bridgerings are one or two carbon atoms. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro ringsare also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). Examples of heterocycles include, but are not limitedto, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazineand tetrahydrofuran.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

As used herein, a “subject in need thereof” is a subject having aneurological disease. In one embodiment, a subject in need thereof hasmultiple sclerosis. A “subject” includes a mammal. The mammal can bee.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog,cat, cow, horse, goat, camel, sheep or a pig. In one embodiment, themammal is a human.

The present invention provides methods for the synthesis of thecompounds of each of the formulae described herein. The presentinvention also provides detailed methods for the synthesis of variousdisclosed compounds of the present invention according to the followingschemes and as shown in the Examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups; therefore, various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, polymorph, hydrate, solvate or co-crystal thereof.

Compounds of the present invention can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry Reactions, Mechanisms, andStructure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentinvention.

Compounds of the present invention can be conveniently prepared by avariety of methods familiar to those skilled in the art. The compoundsof this invention with each of the formulae described herein may beprepared according to the following procedures from commerciallyavailable starting materials or starting materials which can be preparedusing literature procedures. These procedures show the preparation ofrepresentative compounds of this invention.

General Procedure 1

To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5equivalents) in DMF (25 ml per g of MMF) was added Hunigs base (2.0equivalents). The dark brown solution was stirred for 10 minutes, whereturned into a brown suspension, before addition of the alcohol (1.0-1.5equivalents). The reaction was stirred for 18 hours at room temperature.Water was added and the product extracted into ethyl acetate threetimes. The combined organic layers were washed with water three times,dried with magnesium sulphate, filtered and concentrated in vacuo at 45°C. to give the crude product. The crude product was purified by silicachromatography and in some cases further purified by trituration withdiethyl ether to give the clean desired ester product. All alcohols wereeither commercially available or made following known literatureprocedures.

General Procedure 2—Conversion of the Ester Product into theHydrochloride Salt

To a mixture of the ester product in diethyl ether (25 ml per g) wasadded 2M HCl in diethyl ether (1.5 equivalents). The mixture was stirredat room temperature for two hours. The solvent was decanted, morediethyl ether added and the solvent decanted again. The remainingmixture was then concentrated in vacuo at 45° C. and further dried in avacuum oven at 55° C. for 18 hours to give the solid HCl salt.

General Procedure 3

To a 100 mL, one-necked, round-bottomed flask, fitted with a magneticstirrer and nitrogen inlet/outlet, were added 11 mL of an MTBE solutioncontaining freshly prepared mono-methyl fumaryl chloride (4.9 g, 33mmol) and 50 mL of additional MTBE at 20° C. The resulting yellowsolution was cooled to <20° C. with an ice water bath. Then, thealcohol, (33 mmol, 1 eq) was added dropwise, via syringe, overapproximately 10 minutes. The reaction mixture was allowed to stir at<20° C. for 10 minutes after which time the cooling bath was removed andthe reaction was allowed to warm to 20° C. and stir at 20° C.temperature for 6 hours. The reaction was deemed complete by TLC after16 hours at RT. The reaction mixture was filtered through a medium glassfritted funnel to collect the off-white solids. The solids were dried ina vacuum oven at 25° C. overnight to afford the final product as an HClsalt. All alcohols were either commercially available or made followingknown literature procedures.

Chemical Analysis/Procedures

The NMR spectra described herein were obtained with a Varian 400 MHz NMRspectrometer using standard techniques known in the art.

EXAMPLES Example 1(E)-2,2′-((2-((4-methoxy-4-oxobut-2-enol)oxy)ethyl)azanediyl)diaceticacid hydrochloride (1)

To a solution of 2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl methylfumarate (2.52 g, 6.2 mmol) in dioxane (25 ml) was added 2M HCl indioxane (30 ml) and the mixture stirred for 90 hours. The precipitatewas filtered, washed with diethyl ether and dried in a vacuum oven at55° C. for 18 hours to give(E)-2,2′-((2-((4-methoxy-4-oxobut-2-enoyl)oxy)ethyl)azanediyl)diaceticacid hydrochloride, a white solid (1.31 g, 65%).

¹H NMR (300 MHz, MeOD): δ 6.87 (2H, dd, J=16.1 Hz); 4.46-4.53 (2H, m);4.09 (4H, s); 3.79 (3H, s); 3.57-3.63 (2H, m). [M+H]⁺=290.12.

Methyl (2-(methyl(2-(methylsulfonyl)ethyl)amino)ethyl) fumaratehydrochloride (2)

Methyl (2-(N-methylmethylsulfonamido)ethyl) fumarate 2 was synthesizedfollowing general procedure 1 and was converted to the HCl salt methyl(2-(methyl(2-(methylsulfonyl)ethyl)amino)ethyl) fumarate hydrochloride(procedure 2) (1.39 g, 95%).

¹H NMR (400 MHz, DMSO): δ 11.51 (1H, m); 6.83 (2H, dd, J=15.8 Hz); 4.48(1H, bs); 3.24-3.90 (7H, m); 3.07 (3H, s); 2.78 (2H, bs). [M+H]⁺=294.09.

2-(dimethylamino)propyl methyl fumarate hydrochloride (3)

2-(dimethylamino)propyl methyl fumarate 3 was synthesized followinggeneral procedure 1 and was converted to the HCl salt:2-(dimethylamino)propyl methyl fumarate hydrochloride (procedure 2) (329mg, 92%).

1H NMR (300 MHz, DMSO): δ 10.40 (1H, bs); 6.86 (2H, dd, J=15.8 Hz);4.25-4.46 (2H, m); 3.71 (3H, s); 3.34 (1H, s); 2.69 (6H, s); 1.24 (3H,s). [M+H]⁺=216.14.

(E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminiumiodide (4)

To a solution of 2-(dimethylamino)ethyl methyl fumarate 19 (760 mg, 3.7mmol) in diethyl ether (20 ml) was added methyl iodide (246 μl, 3.9mmol). The mixture was stirred at room temperature for 18 hours where aprecipitate slowly formed. The mixture was filtered, washed with diethylether and dried in a vacuum oven at 55° C. for 18 hours to give(E)-2-((4-methoxy-4-oxobut-2-enoyl)oxy)-N,N,N-trimethylethanaminiumiodide, a white solid (1.15 g, 90%).

1H NMR (300 MHz, DMSO): δ 6.80 (2H, dd, J=16.1 Hz); 4.56 (2H, bs);3.66-3.75 (5H, m); 3.11 (9H, s). [M+H]⁺=216.14.

2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate hydrochloride (5)

2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate 5 was synthesizedfollowing general procedure 1 and was converted to the HCl salt:2-(4,4-difluoropiperidin-1-yl)ethyl methyl fumarate hydrochloride(procedure 2) (780 mg, 87%).

¹H NMR (300 MHz, DMSO): δ 11.25 (1H, bs); 6.84 (2H, dd, J=16.1 Hz); 4.50(2H, bs); 3.35-4.00 (8H, m); 3.05-3.30 (2H, m); 2.20-2.45 (3H, s).[M+H]⁺=278.16.

1-(dimethylamino)propan-2-yl methyl fumarate hydrochloride (6)

1-(dimethylamino)propan-2-yl methyl fumarate 6 was synthesized followinggeneral procedure 1 and was converted to the HCl salt1-(dimethylamino)propan-2-yl methyl fumarate hydrochloride (procedure 2)(690 mg, 72%).

¹H NMR (300 MHz, DMSO): δ 10.41 (1H, bs); 6.80 (2H, dd, J=15.8 Hz);5.18-5.33 (1H, m); 3.20-3.55 (2H, m); 3.72 (3H, s); 2.60-2.80 (7H, m);1.18-1.28 (3H, m). [M+H]⁺=216.14.

Methyl (2-thiomorpholinoethyl) fumarate hydrochloride (7)

Methyl (2-thiomorpholinoethyl) fumarate 7 was synthesized followinggeneral procedure 1 and was converted to the HCl salt, methyl(2-thiomorpholinoethyl) fumarate hydrochloride (procedure 2) (623 mg,93%).

¹H NMR (300 MHz, DMSO): δ 11.03 (1H, bs); 6.83 (2H, dd, J=15.6 Hz); 4.50(2H, s); 3.00-3.80 (11H, m); 2.70-2.80 (2H, m). [M+H]⁺=216.14.[M+H]⁺=260.11.

Methyl (2-(phenylamino)ethyl) fumarate hydrochloride (8)

Methyl (2-(phenylamino)ethyl) fumarate 8 was synthesized followinggeneral procedure 1 and was converted to the HCl salt methyl(2-(phenylamino)ethyl) fumarate hydrochloride (procedure 2) (1.80 g,quantitative).

¹H NMR (300 MHz, DMSO): δ 6.50-6.80 (9H, m); 4.29 (2H, t, 4.4 Hz); 3.72(3H, s); 3.45 (2H, t, J=4.5 Hz). [M+H]⁺=250.13.

2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride (9)

2-(dimethylamino)-2-methylpropyl methyl fumarate 9 was synthesizedfollowing general procedure 1 and was converted to the HCl salt,2-(dimethylamino)-2-methylpropyl methyl fumarate hydrochloride(procedure 2) (883 mg, 76%).

¹H NMR (300 MHz, DMSO): δ 10.20 (1H, bs); 6.91 (2H, dd, J=15.6 Hz); 4.29(2H, s); 3.73 (3H, s); 2.57-2.80 (6H, m); 1.32 (6H, s). [M+H]⁺=230.16.

Methyl (2-(methylsulfonyl)ethyl) fumarate (10)

Methyl (2-(methylsulfonyl)ethyl) fumarate 10 was synthesized followinggeneral procedure 1 and (1.01 g, 37%).

¹H NMR (400 MHz, CDCl₃): δ 6.88 (2H, dd, J=16.0 Hz); 4.66 (2H, t, J=5.8Hz); 3.82 (3H, s); 3.38 (2H, t, J=6.0 Hz); 2.99 (3H, s). [M+H]⁺=236.97.

2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate hydrochloride (11)

2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate 11 was synthesizedfollowing general procedure 1 and was converted to the HCl salt2-(1,1-dioxidothiomorpholino)ethyl methyl fumarate hydrochloride(procedure 2) (1.33 g, 87%).

¹H NMR (400 MHz, DMSO): δ 6.79 (2H, dd, J=15.8 Hz); 4.34 (2H, bs); 3.72(4H, s); 2.90-3.70 (11H, m). [M+H]⁺=292.11.

Methyl (2-(methyl(phenyl)amino)ethyl) fumarate hydrochloride (12)

Methyl (2-(methyl(phenyl)amino)ethyl) fumarate 12 was synthesizedfollowing general procedure 1 and was converted to the HCl salt methyl(2-(methyl(phenyl)amino)ethyl) fumarate hydrochloride (procedure 2)(1.76 g, 97%).

¹H NMR (400 MHz, DMSO): δ 6.72-7.40 (5H, m); 6.64 (2H, dd, J=16.0 Hz);4.27 (2H, s); 3.70 (5H, s); 2.97 (3H, s). [M+H]⁺=264.14.

2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (13)

2-(benzyl(methyl)amino)ethyl methyl fumarate 13 was synthesizedfollowing general procedure 1 and was converted to the HCl salt2-(benzyl(methyl)amino)ethyl methyl fumarate hydrochloride (procedure 2)(2.70 g, 96%).

¹H NMR (400 MHz, DMSO): δ 10.65 (1H, bs); 7.39-7.60 (5H, m); 6.82 (2H,dd, J=15.8 Hz); 4.20-4.60 (4H, m); 3.73 (3H, s); 3.27-3.50 (2H, m); 2.69(3H, s). [M+H]⁺=278.16.

2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate (14)

2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate 14 was synthesizedfollowing general procedure 1 (1.03 g, 35%).

¹H NMR (400 MHz, DMSO): δ 6.81 (2H, dd, J=15.8 Hz); 4.36 (2H, t, J=5.3Hz); 3.84 (2H, t, J=5.1 Hz); 3.80 (3H, s); 2.73 (4H, s). [M+H]⁺=256.07.

Methyl (2-(piperidin-1-yl)ethyl) fumarate hydrochloride (15)

Methyl (2-(piperidin-1-yl)ethyl) fumaratehydrochloride 15 wassynthesized following general procedure 3.

¹H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 6.94-6.77 (m, 2H), 4.58-4.51(m, 2H), 3.76 (s, 3H), 3.48-3.36 (m, 4H), 2.94 (dddd, J=15.9, 12.1, 9.2,4.4 Hz, 2H), 1.91-1.64 (m, 5H), 1.37 (dtt, J=16.4, 11.3, 4.9 Hz, 1H).[M+H]⁺=241.93.

Methyl (2-morpholinoethyl) fumarate hydrochloride (16)

Methyl (2-morpholinoethyl) fumaratehydrochloride 16 was synthesizedfollowing general procedure 3.

¹H 1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 6.92 (d, J=15.9 Hz, 1H),6.82 (d, J=15.9 Hz, 1H), 4.60-4.52 (m, 2H), 4.00-3.77 (m, 6H), 3.76 (s,3H), 3.22-3.04 (m, 4H). [M+H]⁺=244.00.

2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumaratehydrochloride (17)

2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl methyl fumaratehydrochloride 17 was synthesized following general procedure 3.

¹H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 6.91 (d, J=15.9 Hz, 1H), 6.82(d, J=15.9 Hz, 1H), 4.58-4.51 (m, 2H), 3.93 (s, 4H), 3.76 (s, 3H),3.57-3.43 (m, 4H), 3.22-3.03 (m, 2H), 2.20-2.02 (m, 2H), 1.89-1.79 (m,2H). [M+H]⁺=300.00.

Methyl (2-(pyrrolidin-1-yl)ethyl) fumarate hydrochloride (18)

Methyl (2-(pyrrolidin-1-yl)ethyl) fumarate hydrochloride 18 wassynthesized following general procedure 3.

¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 6.94 (d, J=15.8 Hz, 1H), 6.82(d, J=15.8 Hz, 1H), 4.53-4.46 (m, 2H), 3.76 (s, 3H), 3.61-3.45 (m, 4H),3.11-2.94 (m, 2H), 2.06-1.79 (m, 4H). [M+H]⁺=228.46.

2-(dimethylamino)ethyl methyl fumarate hydrochloride (19)

2-(dimethylamino)ethyl methyl fumarate hydrochloride 19 was synthesizedfollowing general procedure 3.

¹H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 6.93 (d, J=15.9 Hz, 1H), 6.80(d, J=15.9 Hz, 1H), 4.53-4.45 (m, 2H), 3.75 (s, 3H), 3.44-3.38 (m, 2H),2.77 (s, 5H). [M+H]⁺=201.84.

2-(diethylamino)ethyl methyl fumarate hydrochloride (20)

2-(diethylamino)ethyl methyl fumarate hydrochloride 20 was synthesizedfollowing general procedure 3.

¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 6.90 (d, J=15.8 Hz, 1H), 6.81(d, J=15.9 Hz, 1H), 4.56-4.48 (m, 2H), 3.76 (s, 3H), 3.48-3.38 (m, 2H),3.15 (qq, J=9.7, 5.5, 4.9 Hz, 4H), 1.24 (t, J=7.3 Hz, 6H).[M+H]⁺=230.59.

Reference Compound A

2-(diethylamino)-2-oxoethyl methyl fumarate

2-(diethylamino)-2-oxoethyl methyl fumarate was synthesized followinggeneral procedure 3 and conformed to reported data in U.S. Pat. No.8,148,414.

Example 2 Aqueous Chemical Stability of Several Compounds

Stock solutions of the compounds in acetonitrile oracetonitrile/methanol were prepared at 20 mg/mL. and 20 μL, spiked into3 mL of buffer phosphate (100 mM) and incubated at 37° C. Aliquots (50μL) were sampled at different time points and diluted 20 fold withammonium formate (pH 3.5)/acetonitrile. The diluted samples wereanalyzed by HPLC. The peak areas corresponding to the compounds wereplotted against time and the data were fitted to a first-ordermono-exponential decay where the rate constant and the half-life weredetermined (Table 2). In some cases, in which the half-life is too long(>360 min), an estimated value of the half-life is reported using theinitial slope at low conversion (<10%).

TABLE 2 Compound pH 8 (t½, min)  6 2.0  7 26.0  8 36.0  9 7.0 10 67.011 >240 12 396 14 144 15 3.0 16 20.0 17 11.0 18 5.0 19 6.0 20 5.0Reference 120 Compound A

Example 3 Evaluation of Aqueous Chemical Stability with NMR

The chemical hydrolysis was followed by dissolving the ester inphosphate buffered D₂O (pH 7.9) in an NMR tube, heating the NMR tube to37° C. and periodically recording the spectra. These various speciesproduced by hydrolysis of the diesters were followed over time. SeeFIGS. 1-5.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method of treating a multiple sclerosis orpsoriasis comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (Ib):

wherein: A⁻is a pharmaceutically acceptable anion; R₁ is unsubstitutedC₁-C₆ alkyl; L_(a) is unsubstituted C₁-C₆ alkyl linker, R₃′ isunsubstituted C₁-C₆ alkyl; and R₂ and R₃ are each, independently, H,unsubstituted C₁-C₆ alkyl, unsubstituted C₂-C₆ alkenyl, or unsubstitutedC₂-C₆ alkynyl.
 2. The method of claim 1, wherein R₁ is methyl.
 3. Themethod of claim 2, wherein L_(a) is unsubstituted C₁-C₃ alkyl.
 4. Themethod of claim 2, wherein L_(a) is unsubstituted C₂ alkyl.
 5. Themethod of claim 4, wherein R₂ and R₃ are each, independently,unsubstituted C₁C₆ alkyl.
 6. The method of claim 5, wherein R₃′ ismethyl.
 7. The method of claim 1, wherein the compound is:

wherein A⁻is a pharmaceutically acceptable anion.
 8. The method of claim1, wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 9. The method of claim 2,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 10. The method of claim 3,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 11. The method of claim 4,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 12. The method of claim 5,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 13. The method of claim 6,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.
 14. The method of claim 7,wherein the multiple sclerosis is further selected from the groupconsisting of relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.